Eicosapentaenoic acid ethyl ester soft capsule and preparation process thereof

Abstract

The present application relates to soft capsule preparation technical field, and disclose a kind of eicosapentaenoic acid ethyl ester soft capsule and preparation process, eicosapentaenoic acid ethyl ester soft capsule is composed of content and shell;Content prescription composition is eicosapentaenoic acid ethyl ester and vitamin E;Shell prescription composition and mass ratio are anti-crosslinking gelatin:glycerol:sorbitol:glycine:water=1:(0.15-0.2):0.2:(≤0.01):(0.9-1.056);Anti-crosslinking gelatin is one of succinate plastic type anti-crosslinking gelatin, succinate citrate plastic type anti-crosslinking gelatin, BB 180 / 08 RXL type jialida gelatin, 180 AB 8 ST type rosello gelatin.The present application solves the problem of appearance misting white precipitation of soft capsule shell of stability accelerated 3 months and long-term 3 months soft capsule sample from root cause, and further solves the problem of slow disintegration time limit of soft capsule sample soft capsule stability period.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of soft capsule preparation, in particular to a eicosapentaenoic acid ethyl ester soft capsule and a preparation process. BACKGROUND

[0002] The eicosapentaenoic acid ethyl ester soft capsule is originally researched by Amarin Pharmaceuticals Ireland Ltd, and is used for the auxiliary treatment of statin therapy in clinical practice. It is the only auxiliary drug for the maximum tolerated dose of statins approved by the FDA of the United States, and is also the first drug in the world that can reduce blood lipids and cardiovascular risk. The eicosapentaenoic acid ethyl ester soft capsule was originally researched on May 29, 2023 and was approved for import (Guo Yao Zhu HJ20230058).

[0003] Currently, Anhui Willmann Pharmaceutical Co., Ltd. is researching the eicosapentaenoic acid ethyl ester soft capsule generic drug, and during the sample detection process of the stability acceleration 3 months and the long-term 3 months, it is found that the sample capsule shell appearance has a misting white precipitation phenomenon. In view of this problem, the project team analyzes and researches the potential causes of the soft capsule shell appearance problem from the capsule shell components and process, and puts forward a technical scheme to solve the capsule shell precipitation phenomenon. SUMMARY

[0004] In view of the misting white precipitation problem of the eicosapentaenoic acid ethyl ester soft capsule sample capsule shell appearance in the stability acceleration 3 months and the long-term 3 months, the present application provides a eicosapentaenoic acid ethyl ester soft capsule and a preparation process.

[0005] A eicosapentaenoic acid ethyl ester soft capsule, which is composed of a content and a capsule shell;

[0006] The content prescription composition is eicosapentaenoic acid ethyl ester and vitamin E;

[0007] The capsule shell prescription composition is anti-crosslinking gelatin, glycerol, sorbitol, glycine and water, and the corresponding mass ratio of the prescription composition is 1:(0.15-0.2):0.2:(≤0.01):(0.9-1.056).

[0008] Preferably, the anti-crosslinking gelatin is one of succinate plasticized anti-crosslinking gelatin, succinate citrate plasticized anti-crosslinking gelatin, BB 180 / 08 RXL type Jialida gelatin, and 180 AB 8 ST type Luosailuo gelatin.

[0009] Preferably, the succinate plasticized anti-crosslinking gelatin is prepared by acylation reaction of succinic anhydride functional groups of acylating reagent succinate-based succinic anhydride reagent with amino functional groups in 150 LB 8 type Luosailuo gelatin.

[0010] Preferably, the succinic acid citrate plasticized anti-crosslinking gelatin is prepared by acylating the succinic anhydride functional group of the succinic acid citrate acylating agent with the amino functional group of the 150 LB type Rose Bengal gelatin.

[0011] Preferably, the ethyl eicosapentaenoate soft capsule is composed of 70-90wt% content and 10-30wt% capsule shell.

[0012] Preferably, the mass ratio of ethyl eicosapentaenoate to vitamin E is 1:(0.001-0.003).

[0013] The preparation process of the ethyl eicosapentaenoate soft capsule comprises the following steps:

[0014] Step one, content preparation: according to the prescription amount of the content, vitamin E is added to ethyl eicosapentaenoate under nitrogen protection, and stirred uniformly at room temperature to obtain the content;

[0015] Step two, sol preparation: purified water is weighed in a sol tank and heated, and when the temperature of the purified water reaches 55-65 DEG C, glycerol is added and stirred uniformly, then sorbitol and glycine are added, and the temperature is further increased to 80-90 DEG C, then gelatin is added, and stirred to make the gelatin completely melt into a gel liquid, and after vacuum degassing, it is placed at a constant temperature of 50-60 DEG C for standby;

[0016] Step three, the content and the sol are subjected to soft capsule preparation by a soft capsule pill press to obtain the ethyl eicosapentaenoate soft capsule.

[0017] The ethyl eicosapentaenoate soft capsule is used as an auxiliary drug for clinical statin treatment.

[0018] The present application has the following advantages:

[0019] Firstly, by reducing the proportion of glycine in the capsule shell of the ethyl eicosapentaenoate soft capsule sample, the problem of misting and whitening precipitation of the capsule shell of the ethyl eicosapentaenoate soft capsule sample is solved from the root.

[0020] Secondly, the acid anhydride polyester base reagent (succinic acid citrate base reagent or succinic acid citrate base reagent) is used to modify the low-cost Rose Bengal gelatin (type 150 LB 8) to obtain a plasticized anti-crosslinking gelatin, which is used as an optimized component of the ethyl eicosapentaenoate soft capsule sample capsule shell prescription, and the problem of delayed disintegration of the ethyl eicosapentaenoate soft capsule sample during the stability period is solved. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 The appearance of the soft capsule is 0 days.

[0022] Figure 2 Appearance of soft capsules at room temperature after 3 months of accelerated stability.

[0023] Figure 3 Appearance of soft capsules at room temperature after 3 months of long-term stability.

[0024] Figure 4 Infrared spectrum of the precipitate on the surface of the capsule shell.

[0025] Figure 5 Infrared spectrum of the capsule shell without abnormalities.

[0026] Figure 6 Infrared spectrum of gelatin.

[0027] Figure 7 Infrared spectrum of glycerol.

[0028] Figure 8 Infrared spectrum of sorbitol.

[0029] Figure 9 Infrared spectrum of glycine.

[0030] Figure 10 Comparison of the infrared spectra of glycine and the precipitate. DETAILED DESCRIPTION

[0031] The problems discovered during the research process of eicosapentaenoic acid ethyl ester soft capsules generic drugs are as follows:

[0032] The appearance of soft capsules at 0 days is shown in Figure 1 The appearance of the capsule shell of the sample after 3 months of accelerated stability is shown in Figure 2 The appearance of the capsule shell of the sample after 3 months of long-term stability is shown in Figure 3 ;

[0033] The results of Figure 2 and Figure 3 show that the appearance of the capsule shell of the samples after 3 months of accelerated stability and 3 months of long-term stability has a misting and white precipitate phenomenon.

[0034] In view of the above-mentioned problem of misting and white precipitate on the appearance of the capsule shell, investigation and research were carried out, and the specific process and results are as follows:

[0035] Select soft capsules with obvious white precipitate, and perform infrared analysis on the precipitate on the surface of the capsule shell, and the analysis results are shown in Figure 4 , and perform infrared analysis on the capsule shell without abnormalities, and the analysis results are shown in Figure 5 ;

[0036] The analysis results of Figure 4 and Figure 5 lead to the following conclusions:

[0037] (1) From the NH and amide C=O peaks, it is determined that the precipitate is completely separated from the gelatin base;

[0038] (2) The precipitate contains 1750 cm -1 saturated ester groups;

[0039] (3) The precipitate does not contain NH and -OH;

[0040] (4) The precipitate has three characteristic absorptions of 680 cm -1 , 890 cm -1 and 930 cm -1

[0041] Further, each component in the capsule shell prescription is subjected to infrared detection, and the analysis results are shown in Figure 6 , Figure 7 , Figure 8 and Figure 9 , which are compared with the detection results of the precipitate one by one, and the infrared spectrum comparison results of glycine and the precipitate are shown in Figure 10 ;

[0042] By comparing the absorption characteristic peaks of the key functional groups in the infrared spectrum, it is confirmed that the precipitate of the soft capsule shell is glycine, and the -OH characteristic absorption peak is not seen in the spectrum of the precipitate, indicating that sorbitol and glycine in the capsule shell do not undergo esterification.

[0043] Glycine in the capsule shell serves as an antioxidant on the one hand, and on the other hand, it affects the disintegration time limit of the soft capsule during the stability period by blocking the main binding site amino group in the gelatin cross-linking reaction, and the reason for the precipitation of glycine is that glycine is in a supersaturated state in the capsule shell. By calculation, the saturation solubility ratio of glycine and gelatin at 0°C is 0.0105 (based on 5% moisture content of the capsule shell), and the saturation solubility ratio of glycine and gelatin at 25°C is 0.0187 (based on 5% moisture content of the capsule shell);

[0044] In order to balance the disintegration time limit of the soft capsule during the stability period and the possible precipitation risk of glycine, there are two optimization schemes for the prescription of the eicosapentaenoic acid ethyl ester soft capsule shell:

[0045] First, adjust the ratio of glycine to gelatin to 0.01 (i.e. glycine does not reach saturation state under relatively extreme conditions, and under normal temperature storage conditions, it is about 50% of the saturation concentration), that is, the preferred composition of the capsule shell prescription is gelatin: glycerol: sorbitol: glycine: water = 1:0.2:0.2:0.01:0.9;

[0046] ​Secondly, the proportion of glycine is reduced to 0.005, which is 30% of the saturated concentration ratio. The amount of glycine in the capsule shell is 30% of the saturated solubility. The risk of glycine precipitation during the stable period is lower. However, the amount of glycine is reduced by 6 times compared with the current prescription, which may affect the stability of the soft capsule. The risk of disintegration time limit during the stability of the soft capsule is higher. At this time, the succinic anhydride reagent is used to modify the gelatin. The amino group is increased by reacting with the amino group in the gelatin. The content of free amino group in the gelatin is reduced. That is, the anti-crosslinking treatment of gelatin can reduce the risk of disintegration time limit during the stability of the soft capsule and the risk of glycine precipitation.

[0047] Therefore, it is proposed to solve the problem of capsule precipitation by reducing the proportion of glycine in the capsule shell. Based on this, a monosuccinic anhydride succinate-based reagent is developed and synthesized. The succinate plastic anti-crosslinking gelatin is obtained by modifying the gelatin with the monosuccinic anhydride succinate-based reagent. Further, a monosuccinic anhydride succinate citrate reagent is developed and synthesized. The succinate citrate plastic anti-crosslinking gelatin is obtained by modifying the gelatin with the monosuccinic anhydride succinate citrate reagent to reduce the risk of disintegration time limit during the stability of the soft capsule. Example 1

[0048] A soft capsule of ethyl eicosapentaenoate consists of 75wt% content and 25wt% capsule shell.

[0049] In the content prescription, the mass ratio of the content of the components is ethyl eicosapentaenoate: vitamin E = 1:0.002.

[0050] The specific experimental scheme of the optimization experiment of the ethyl eicosapentaenoate soft capsule shell prescription is shown in Table 1.

[0051] Table 1 Optimization scheme of ethyl eicosapentaenoate soft capsule shell prescription

[0052]

[0053] The price of Rosebush gelatin (model 150 LB 8) is 83 yuan / kg.

[0054] The price of Gelita gelatin (model BB 180 / 08 RXL) is 270 yuan / kg.

[0055] The price of Rosebush gelatin (model 180 AB 8 ST) is 90 yuan / kg.

[0056] Gelita gelatin (model BB 180 / 08 RXL) and Rosebush gelatin (model 180 AB 8 ST) are both anti-crosslinking gelatin, and have the same anti-crosslinking mechanism. Example 2:

[0057] The preparation process of eicosapentaenoic acid ethyl ester soft capsules includes the following steps:

[0058] Step one, content preparation: according to the prescription amount of the content, vitamin E is added to eicosapentaenoic acid ethyl ester under nitrogen protection, and stirred uniformly at room temperature to obtain the content;

[0059] Step two, sol preparation: purified water is weighed in a sol tank and heated, and when the temperature of the purified water reaches 60°C, glycerol is added and stirred, then sorbitol and glycine are added, and the temperature is continued to rise to 85°C, then gelatin is added, and stirred for 2h to make the gelatin completely melt into a gel liquid. After vacuum degassing bubbles, it is placed at 60°C for standby;

[0060] Step three, the content and sol are subjected to soft capsule preparation by a soft capsule pill press to obtain 1g eicosapentaenoic acid ethyl ester soft capsules. Example three:

[0061] The peroxide value index of the eicosapentaenoic acid ethyl ester soft capsule sample at 0 days and after 1.5 months or 1 month of accelerated stability test is detected according to the peroxide value detection method specified in the fatty acids and fatty oils determination method of Chinese Pharmacopoeia 2020 edition general rules 0731, and the disintegration time limit index of the sample is detected according to the disintegration time limit inspection method of Chinese Pharmacopoeia 2020 edition general rules 0921;

[0062] The eicosapentaenoic acid ethyl ester soft capsule sample is detected for whether there is misting, whitening and precipitation after 3 months of accelerated stability test and 3 months of long-term test;

[0063] The above experimental results are shown in Table 2 as follows:

[0064] Table 2 Experimental results of eicosapentaenoic acid ethyl ester soft capsules

[0065]

[0066] Among them, the accelerated test conditions are: temperature 40°C±2°C, relative humidity 75%±5%; the long-term test conditions are: temperature 25°C±2°C, relative humidity 60%±10%;

[0067] From the above experimental results, the following conclusions can be drawn: the combination of the control means of reducing the proportion of glycine and the technical improvement means of anti-crosslinking treatment of gelatin can realize the beneficial technical effects of simultaneously reducing the disintegration time limit risk and glycine precipitation risk during stability.

[0068] Experimental example one:

[0069] The succinic monoanhydride succinate reagent is synthesized by the nucleophilic substitution reaction between the acyl chloride functional group of succinic monoethyl acyl chloride and the hydroxyl functional group of L-malic acid, and the succinic monoethyl acyl chloride activates the two carboxylic acid functional groups of L-malic acid to promote the dehydration reaction, thereby generating the succinic monoanhydride succinate reagent;

[0070] The experimental steps for synthesizing the succinic monoanhydride succinate reagent are as follows: L-malic acid 13.4 g and succinic monoethyl acyl chloride 30 mL are heated to 80°C and stirred for 5 h, unreacted substances are removed by rotary evaporation, 100 mL of petroleum ether / chloroform (V / V=3 / 1) is added, and then the mixture is left to stand, precipitate, filter, and the filter cake is washed with petroleum ether and dried to obtain the succinic monoanhydride succinate reagent, and the chemical structural formula thereof is as follows:

[0071] ;

[0072] The hydrogen spectrum characterization result of the succinic monoanhydride succinate reagent is as follows: 1 H NMR (400 MHz, CDCl3, δ, ppm): 6.19-6.22 (t, 1H), 4.09-4.13 (m, 2H), 2.95-3.25 (m, 2H), 2.60-2.75 (m, 4H), 1.20-1.23 (t, 3H).

[0073] Experimental Example Two

[0074] The succinic monoanhydride succinate reagent is synthesized by the nucleophilic substitution reaction between the acyl chloride functional group of succinic monoethyl acyl chloride and the hydroxyl functional group of L-malic acid, and the succinic monoethyl acyl chloride activates the two carboxylic acid functional groups of L-malic acid to promote the dehydration reaction, thereby generating the succinic monoanhydride succinate reagent;

[0075] The succinic monoanhydride succinate reagent is synthesized by the nucleophilic substitution reaction between the acyl chloride functional group of succinic monoethyl acyl chloride and the hydroxyl functional group of L-malic acid, and the succinic monoethyl acyl chloride activates the two carboxylic acid functional groups of L-malic acid to promote the dehydration reaction, thereby generating the succinic monoanhydride succinate reagent;

[0076] The experimental steps for synthesizing the succinic monoanhydride succinate reagent are as follows:

[0077] The acyl chloride tetraester monomer is obtained by the nucleophilic substitution reaction between the hydroxyl functional group of citric acid triethyl ester and the acyl chloride functional group of succinyl chloride, and the succinyl chloride activates the two carboxylic acid functional groups of L-malic acid to promote the dehydration reaction, thereby generating the succinic monoanhydride succinate reagent;

[0078] L-malic acid 4 g, acyl chloride tetra ester base monomer 23.65 g and N,N-dimethylformamide 60 mL were heated to 90℃, stirred for 5 h, distilled under reduced pressure, 100 mL petroleum ether / chloroform (V / V=3 / 1) was added to the crude product, and then it was left to stand, precipitated, filtered, the filter cake was washed with petroleum ether, and dried to obtain a succinate citrate succinate reagent, and its chemical structural formula is:

[0079] ;

[0080] The hydrogen spectrum characterization result of the succinate citrate succinate reagent is: 1 H NMR (400 MHz, CDCl3, δ, ppm): 6.15-6.17 (t, 1H), 4.19-4.23 (m, 2H), 4.04-4.08 (m, 4H), 2.95-3.29 (m, 6H), 2.65-2.76 (m, 4H), 1.25-1.27 (t, 3H), 1.15-1.17 (t, 6H).

[0081] Experimental Example Three:

[0082] Succinate plasticized anti-crosslinking gelatin: a succinate plasticized anti-crosslinking gelatin is prepared by acylating reaction between the succinic anhydride functional group of the succinate citrate succinate reagent and the amino functional group in the gelatin;

[0083] The experimental steps for preparing the succinate plasticized anti-crosslinking gelatin are as follows: Rose Bengal gelatin (model 150 LB 8) is prepared into a gelatin solution (the mass ratio of gelatin to distilled water is 1:5) with distilled water, and then it is placed into a constant temperature heating magnetic stirrer to be dissolved at 45℃ under stirring. After complete dissolution, it is taken out and cooled to room temperature, and then 1 mol / L sodium hydroxide solution is used to adjust the pH value to 9.5. The succinate citrate succinate reagent is added (the mass ratio of the succinate citrate succinate reagent to the gelatin is 1:8), 1 mol / L sodium hydroxide solution is added dropwise to stabilize the pH value at 9.5, and then it is heated to 45℃ for stirring reaction for 2 h. It is then moved into a dialysis bag, dialyzed in distilled water for 48 h, taken out after dialysis, and then air-dried at 40℃ until the weight is constant to obtain the succinate plasticized anti-crosslinking gelatin.

[0084] Experimental Example Four:

[0085] Succinate citrate plasticized anti-crosslinking gelatin: a succinate citrate plasticized anti-crosslinking gelatin is prepared by acylating reaction between the succinic anhydride functional group of the succinate citrate succinate reagent and the amino functional group in the gelatin;

[0086] The preparation of succinic citrate plasticized anti-crosslinking gelatin is only different from the experimental steps of the preparation of succinate plasticized anti-crosslinking gelatin in that the succinic citrate anhydridized succinic citrate reagent is used instead of the succinic anhydridized succinate reagent.

Claims

1. An ethyl eicosapentaenoic acid (EEA) soft capsule, characterized in that, Ethyl eicosapentaenoic acid soft capsules consist of contents and a shell; The contents are formulated with ethyl eicosapentaenoate and vitamin E; The capsule shell formulation consists of anti-crosslinking gelatin, glycerin, sorbitol, glycine, and water, with a mass ratio of 1:(0.15-0.2):0.2:(≤0.01):(0.9-1.056). The anti-crosslinking gelatin is either succinate-reinforced anti-crosslinking gelatin or succinate-citrate-reinforced anti-crosslinking gelatin. Succinate-modified anti-crosslinking gelatin is prepared by acylation reaction of the succinic anhydride functional group of the acylation reagent monosuccinic anhydride succinate group with the amino functional group in 150 LB 8 type Rousselot gelatin. The chemical structural formula of the monosuccinic anhydride succinate reagent is: ； The succinic acid citrate-modified anti-crosslinking gelatin is prepared by acylation reaction between the succinic anhydride functional group of the acylation reagent monosuccinic anhydride succinic acid citrate reagent and the amino functional group in 150 LB 8 type Rousselot gelatin. The chemical structural formula of the monosuccinic anhydride succinic acid citrate reagent is: 。 2. The ethyl eicosate soft capsule according to claim 1, characterized in that, The preparation method of monosuccinic anhydride succinate group reagent is as follows: the acyl chloride functional group of monoethyl succinate chloride undergoes a nucleophilic substitution reaction with the highly nucleophilic hydroxyl functional group in L-malic acid, and the activation of monoethyl succinate chloride promotes the dehydration reaction of the two carboxylic acid functional groups of L-malic acid to generate monosuccinic anhydride succinate group reagent.

3. The ethyl eicosate soft capsule according to claim 1, characterized in that, The preparation method of the monosuccinic anhydride succinic acid citrate reagent is as follows: A tetraester acyl chloride monomer was obtained by nucleophilic substitution of hydroxyl and acyl chloride functional groups by reacting equimolar amounts of triethyl citrate with succinyl chloride. The acyl chloride functional group of the tetraester acyl chloride monomer undergoes a nucleophilic substitution reaction with the highly nucleophilic hydroxyl functional group in L-malic acid, and the activation of the tetraester acyl chloride monomer promotes the dehydration reaction of the two carboxylic acid functional groups of L-malic acid to generate monosuccinic anhydride succinic acid citrate reagent.

4. The ethyl eicosate soft capsule according to claim 1, characterized in that, Ethyl eicosapentaenoic acid soft capsules consist of 70-90 wt% contents and 10-30 wt% capsule shell.

5. The ethyl eicosate soft capsule according to claim 1, characterized in that, The mass ratio of eicosapentaenoic acid ethyl ester to vitamin E in the contents formulation is 1:(0.001-0.003).

6. The preparation process of an ethyl eicosapride soft capsule according to any one of claims 1-5, characterized in that, Includes the following steps: Step 1, Content Preparation: According to the prescribed amount of the contents, under nitrogen protection, add vitamin E to ethyl eicosapentaenoic acid and stir evenly at room temperature to obtain the contents. Step 2, Sol preparation: Weigh purified water into a sol tank and heat it. When the temperature of the purified water reaches 55-65℃, add glycerin and stir evenly. Then add sorbitol and glycine. Continue to heat to 80-90℃ and add anti-crosslinking gelatin. Stir until the anti-crosslinking gelatin is completely melted into a gel solution. After vacuum degassing, let it stand at a constant temperature of 50-60℃ for later use. Step 3: The contents and sol are processed into soft capsules using a soft capsule compression machine to obtain ethyl eicosapentaenoic acid soft capsules.

7. An ethyl eicosapride soft capsule according to any one of claims 1-5, characterized in that, Ethyl eicosapentaenoic acid (EECA) soft capsules are used as an adjunct to statin therapy in clinical practice.

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